title: Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling.
abstract: Nitric oxide (NO) is a ubiquitous mediator of inflammation and immunity, involved in the pathogenesis and control of infectious diseases, autoimmunity, and cancer. We observed that the expression of nitric oxide synthase-2 (NOS2/iNOS) positively correlates with Th17 responses in patients with ovarian cancer (OvCa). Although high concentrations of exogenous NO indiscriminately suppress the proliferation and differentiation of Th1, Th2, and Th17 cells, the physiological NO concentrations produced by patients’ myeloid-derived suppressor cells (MDSCs) support the development of RORγt(Rorc)+IL-23R⁺IL-17⁺ Th17 cells. Moreover, the development of Th17 cells from naive-, memory-, or tumor-infiltrating CD4+ T cells, driven by IL-1β/IL-6/IL-23/NO-producing MDSCs or by recombinant cytokines (IL-1β/IL-6/IL-23), is associated with the induction of endogenous NOS2 and NO production, and critically depends on NOS2 activity and the canonical cyclic guanosine monophosphate (cGMP)–cGMP-dependent protein kinase (cGK) pathway of NO signaling within CD4⁺ T cells. Inhibition of NOS2 or cGMP–cGK signaling abolishes the de novo induction of Th17 cells and selectively suppresses IL-17 production by established Th17 cells isolated from OvCa patients. Our data indicate that, apart from its previously recognized role as an effector mediator of Th17-associated inflammation, NO is also critically required for the induction and stability of human Th17 responses, providing new targets to manipulate Th17 responses in cancer, autoimmunity, and inflammatory diseases.
authors.affiliation: Department of Surgery, University of Pittsburgh, PA 15224, USA.
authors.forename: Nataša
authors.initials: N
authors.lastname: Obermajer
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wong
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
authors.forename: Kong
authors.initials: K
authors.lastname: Chen
authors.forename: Melanie
authors.initials: M
authors.lastname: Scott
authors.forename: Shabaana
authors.initials: S
authors.lastname: Khader
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
chemical_list: D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP